Association Between Cervical Cancer Screening Guidelines and Preterm Delivery Among Females Aged 18 to 24 Years

This cross-sectional study examines the association between the number of guideline-recommended screenings for cervical cancer and the risk of preterm delivery in females aged 18 to 24 years.

There was strong correlation between BRFSS reported screening rates and the Recommended Number of Screenings variables for both ever-Pap and 3-year Pap measures (Pearson correlation coefficients 0.88 and 0.89 respectively; Supplemental eFigure 4). Similarly high degrees of correlation were observed across different race and ethnicity groups (Supplemental eFigure 5). Because actual adherence is typically lower than guideline recommendations, the Recommended Number of Screenings likely represents an overestimate of the number of screenings an individual woman received.

eAppendix 2: Gestational Age Estimate
We opted to use the Last Menstrual Period (LMP) definition for defining gestational age because it was consistent over time across the duration of our study period. It is important to note that this definition is not the current standard used by the CDC. The obstetric estimate has been the standard since 2014 and the LMP definition has been shown to result in higher rates of PTD. However, previous literature including the CDC report above shows a high degree of correlation reported between the two measures. While the LMP-based definition may represent an overestimation of preterm birth rates, there is a corresponding documentation of underestimation of neonatal mortality for infants delivered preterm. A thorough comparison of the two measures is available from the CDC: https://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_05.pdf. The obstetric estimate is preferred for current use and should be used for future research in this area as possible.

eAppendix 3: Difference-in-Differences Estimation Assumptions and Extensions
A key assumption underlying causal identification from DiD models is an assumption of parallel trends in untreated outcomes, or in other words, that in the absence of treatment, the difference between the 'treatment' and 'control' group would be constant over time. Recent literature suggests that standard two-way fixed effects DiD models with multiple treatment periods may be biased due to variation in treatment timing and potentially heterogeneous treatment effects over time. In our analysis, the bias would occur if the impact of recommended screenings affected PTD risk differentially in different years, and if the treatment effect itself varied over time. Several recent methods have been developed to relax the standard "parallel trends" assumption and address the issues stemming from variation in treatment timing. 1,2 We augment our analysis with an estimation using a recent method developed by Callaway and Sant'Anna (2021) which addresses these issues. This approach relies on having a binary treatment indicator, and thus we first transform our Recommended Number of Screenings variable accordingly.
Specifically, we create a binary indicator that is equal to 1 if a mother is recommended fewer than 2 screenings by the time of childbirth, and 0 otherwise. Thus, in this analysis we are studying the relationship between having fewer than 2 recommended screenings and the risk of PTD. Given that our baseline analysis found that an additional screening was associated with a higher risk of PTD, we expect to see that having fewer than 2 screenings (as opposed to 2 or more) is associated with a lower risk of PTD.
The results of this model using techniques developed by Callaway-Sant'Anna with the same controls from our main model yielded an average treatment effect on the treated (ATT) of -0.063 pp (95% CI: 0.097, -0.222, p-value 0.184), shown in Supplemental eFigure 6. The event-study figure provides evidence against pre-trends of concern and qualitatively supports that being recommended fewer than 2 screenings reduces the likelihood of PTD, in alignment with our baseline result that being recommended higher numbers of screenings increases the likelihood of PTD.

eAppendix 4: Potential Maternal HPV Vaccine Exposure Subanalysis
To investigate whether Maternal HPV Vaccine exposure might mediate any of the effects, we conducted a subgroup analysis between the cohort of females who were ever eligible for (and therefore potentially exposed to) the HPV vaccine. The first-generation Gardasil vaccine gained FDA approval in 2006 and beginning in 2007 was recommended for children aged 11 and 12. Gardasil 9 was approved by the FDA in 2014 and has gradually become the only available option in the US. Various schedules for missed and catch-up vaccination recommendations for individuals 13 and older have been proposed. Initial schedules proposed catch-up vaccinations up to age 18, then later iterations gradually relaxed the upper limit to age 26, and currently allow for catch-up vaccinations to age 45 upon physician-patient discretion.
To model potential HPV vaccine exposure, we include a dummy variable for mothers who were born in 1989 or later (or in other words mothers who would have been 11-18 years old from 2007 onwards and therefore eligible for potential vaccination). Our results, presented in Supplemental eTable 4, show that effects may be stronger for younger cohorts (i.e., those likely exposed to the HPV vaccine), though the estimates are not statistically significant. However, because HPV vaccine uptake remained very low for several years following its rollout (and was found to have significant racial disparities in its dissemination and uptake), it is also possible the trends are a reflection of heterogeneity along the many other dimensions by which cohorts differ over time. 3 Because of this major limitation, we are hesitant to draw conclusions about the role of vaccine exposure from this limited preliminary analysis.

eTable 1. Recommended Number of Screens by Age at Birth by Childbirth Year
This

. Effect of Cervical Cancer Screenings on Neonatal Outcomes, Extended Table with Coefficients
Controls included individual mother's age, birth year, mother's marital status, number of maternal prenatal visits, maternal hypertension, maternal diabetes, mother's race, and mother's education. Number of recommended screenings refers to the estimated number of recommended Pap Tests that an individual should have received based on age and childbirth year, assuming they had followed the guidelines in place prior to giving birth. Standard errors were clustered by mother's age and childbirth year [95% CIs listed in brackets]. *p<0.05, **p<0.01, ***p<0.001

. HPV Exposure Subgroup Analysis
This subgroup analysis compared mothers who gave birth before 1989 and therefore were unlikely to have received the HPV vaccine and mother's born later who plausibly could have been exposed to the vaccine. Controls included individual mother's age, birth year, mother's marital status, number of maternal prenatal visits, maternal hypertension, maternal diabetes, mother's race, and mother's education. Number of recommended screenings refers to the estimated number of recommended Pap tests that an individual should have received based on age and childbirth year, assuming they had followed the guidelines in place prior to giving birth. Standard errors were clustered by mother